Matrix metalloproteinase (hereinafter referred to as MMP) is a zinc-dependent endopeptidase which functions extracellularly (see Non-Patent Document 1). MMP degrades extracellular matrix (EMC) (for example, elastin, collagen, gelatine, laminin, and fibronectin), which is essential mainly in maintaining structures of elastic fibers or tissue in vivo under physiological conditions, and functions to facilitate the remodeling of normal tissue or the repair of tissue injury. In addition, under physiological conditions, the amount of mRNA and protein, or enzyme activity of MMP are controlled by various mechanisms so as not to degrade the extracellular matrix excessively. As for the endogenous enzyme inhibitor of MMP, tissue inhibitor of metalloproteinase (TIMP) has been known.
On the other hand, It has been known that, in pathological conditions of oncogenic angiogenesis, chronic rheumatoid arthritis, vascular intimal thickening, vascular atherosclerosis, hemorrhagic apoplexy, acute myocardial infarction, chronic heart failure, aneurysm, cancer metastasis, adult respiratory distress syndrome, asthma, interstitial pulmonary fibrosis, chronic rhinosinusitis, bronchitis or chronic obstructive pulmonary disease (COPD), mechanisms to control the MMP activation fails, and the disease state is exacerbated due to excess EMC degradation (see Non-Patent Documents 1 and 2). Accordingly, if the control mechanisms against the MMP activation can be repaired to a normal state, it would appear to be useful for treating the above-mentioned diseases.
MMP has isozymes of 20 kinds or more. In particular, it is proven that mRNA, protein and the activity of MMP-9 (Gelatinase B) having the molecular weight of 92 kDa are induced in the above-mentioned diseases. MMP-9 is known to not only degrade EMC such as collagen type IV and elastin, but also exacerbate an inflammatory response by degrading cytokines (for example, interleukin (IL)-1β, IL-8, tumor growth factor (TGF)-β) and following by enhancing the said cytokines activity. Furthermore, the MMP degrades endogenous protease inhibitors (e.g. tissue factor protease inhibitor, α 1-antitrypsin, and α 1-antichymorypsin), activates protease cascades, and thereby further exacerbates the disease state.
In general, COPD is a disease characterized by an obstructive ventilator impairment, which is caused by bronchitis, emphysema, or both of them. In GOLD (Global Initiative for Chronic Obstructive Lung Disease) which is an international treatment guideline of COPD, it is defined that “COPD is a disease which is characterized by airflow limitation that is not fully reversible, and the airflow limitation is usually progressive and associated with an abnormal inflammatory response of the lung to noxious particles or gases”. This suggests that improvement of inflammatory response can lead to a causal therapy.
Emphysema in COPD is a symptom in which the walls of alveoli are broken down and the microstructure of the alveoli become hollow. Emphysema decreases the gas exchange rate and the elastic recoil of the whole lung, and the lung function is finally depressed. It has been known that the onset of emphysema intimately involves MMP-9 and MMP-12 released from the resident or newly infiltrating inflammatory cells in lung (for example, alveolar macrophage and neutrophil) which are activated by smoking, air pollution, noxious gases or the like (see Non-Patent Document 3).
MMP-9 is produced and activated in cells involved in emphysema such as neutrophils, alveolar macrophages, and epithelial cells by inflammatory stimuli such as TNF α (Tumor Necrosis Factor) and IL-1 (Interleukin-1). It was reported that the amount of MMP-9 increased in correlation with the decrease of lung function in patients with COPD. (See Non-Patent Document 4)
For the present pharmacotherapy, airway dilators (anticholinergic agent, β2 receptor agonist etc.) are widely clinically used which show the effect in improving the patients' QOL, but are still not satisfactory.
As the method of specifically decreasing the functions of MMP-9, a method for inhibiting the enzyme activity, and a method for inhibiting the production of MMP-9 mRNA and protein associated with inflammatory response are considered. With regard to the enzyme inhibitor, several compounds have been found so far in the prior art, which have been tried for oncogenic angiogenesis, metastasis, chronic obstructive pulmonary disease (COPD) or the like. However, it has not been accomplished to launch them as a medicine. In particular, an enzyme inhibitor has not yet been practically used as a medicine out of concern of a side effect on skeletal muscles due to its prolonged administration.
With regard to the antibiotic having a macrolide skeleton (erythromycin, clarithromycin, roxithromycin and azithromycin), anti-inflammatory activity in vitro has been reported.
In addition, roxithromycin has been reported to have an inhibitory effect on MMP-9 production (see Non-Patent Document 3), the 50% inhibitory concentration (IC50) value is 10 μM or more but it is insufficient for a medicine that actively treats the above-mentioned diseases. Further, since roxithromycin has a strong antibacterial activity, there occur problems such as gastrointestinal disorders with changes in intestinal flora by chronic administration, development of resistant bacteria, and the like. From this viewpoint, use of the macrolide derivative which has an antibacterial activity for the above-mentioned diseased is limited. That is, in fact, there is no example of completely separating the antibacterial activity from other required activities (inhibitory activity against MMP-9 production or the like).
Furthermore, the art in which azithromycin is used for the treatment of neutrophil-dominated non-infectious inflammatory diseases including COPD is disclosed (see Patent Document 1), but the antibacterial activity had not been separated.
There are reports about a compound which derivatizes a hydroxy group at the 2′-position of desosamine bonded to the 5-position of erythromycin-based antibiotic (see Patent Document 2 and Non-Patent Document 6), but there is no description on a separation of the antibacterial activity from the inhibitory activity of MMP-9 production.    Patent Document 1: WO 02/087596    Patent Document 2: Japanese Patent Application Laid-Open No. 55-151598    Non-Patent Document 1: Circ. Res., 90:520-530 (2003)    Non-Patent Document 2: Am. J. Respir. Cell Mol. Biol., 28, 12-24 (2003)    Non-Patent Document 3: Nature Reviews/Drug Discovery, Vol. 1, 437-446 (2002)    Non-Patent Document 4: Am. J. Respir. Cell Mol. Biol. 26, 602-609 (2002)    Non-Patent Document 5: Mediator of Inflammation, 13, 313-319 (2004)    Non-Patent Document 6: Heterocycles, Vol. 31, No. 2, 305-319 (1990)